Innate immunity, therapeutic targets and monoclonal antibodies in SARS-CoV-2 infection

Abstract

COVID-19 (coronavirus disease 2019), caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), stands as one of the most severe pandemics the world has ever faced in recent times. SARS-CoV-2 infection exhibits a wide range of symptoms, varying from severe manifestations to mild cases and even asymptomatic carriers. This diversity stems from a multitude of factors, including genetic predisposition, viral variants, and immune status. During SARS-CoV-2 infection, the immune system engages pattern recognition receptors, setting off a series of intricate signalling cascades. These cascades culminate in the activation of innate immune responses, including induction of type I and type III interferons. The emerging variants of SARS-CoV-2 pose challenges to the innate immune system defense. Therefore, investigating the innate immune response is crucial for effectively combating SARS-CoV-2 and its variants. The cyclic guanosine monophosphate-adenosine monophoshate synthase-stimulator of interferon genes (cGAS-STING) pathway, a critical innate immune mechanism, represents a promising target for intervention at multiple stages to reduce the severity and progression of SARS-CoV-2 infection. This review explores innate immunity in SARS-CoV-2 infection and other immune responses critical for SARS-CoV-2 defence. As part of the therapeutic approach, we extend our review to highlight monoclonal antibodies (mAbs) as emerging and effective therapeutics for controlling SARS-CoV-2 by targeting different stages of the innate immune system. A diverse range of mAbs has been explored to address specific targets within the innate immune pathways. A deep understanding of innate immunity and targeted monoclonal therapeutics will be instrumental in combating viruses and their variants, laying the foundation for enhanced treatment and therapeutic strategies.

Keywords: Innate immunity; Monoclonal antibody; SARS-CoV-2; STINGs; Signaling molecules.

Figure 1. SARS-CoV-2 structure, viral host interaction and virion formation in the host cells.

(A) The SARS-CoV-2 structure, and maturation involve the formation of new membranous structures known as “replication organelles” near the cell nucleus. These structures are surrounded by double membranes and are believed to originate from the endoplasmic reticulum (ER). These organelles serve as a location for viral replication complexes, isolating them from the cells innate immune response. The process of virus assembly starts with the synthesis of viral proteins and genomic RNA at the replication site. These components are then transported, through an unknown mechanism, to the ER-Golgi intermediate compartment (ERGIC), where assembly and budding of new viruses occur. (B) The SARS-CoV-2 spike (S) protein is a crucial component of the virus responsible for binding to human cells and facilitating infection. It consists of various subdomains with distinct functions. One of the essential parts of the S protein is the receptor-binding domain (RBD), responsible for recognizing and binding to the human cell receptor ACE2 (Angiotensin-Converting Enzyme 2). The RBD has three distinct antigenic sites (AS-1, AS-2, and AS-3), which are regions that can trigger an immune response. RBD can be one of the targets for the monoclonal antibodies as depicted above (Figure created on biorender.com).

Figure 2. Molecular mechanisms of SARS-CoV-2-induced pulmonary injury via apoptotic pathways.

SARS-CoV-2 infection triggers multiple apoptotic pathways. The viral Orf3a protein activates PERK signaling, which upregulatesBak/Bax, leading to the activation ofcaspase-9 and intrinsic apoptotic pathways. Additionally, viral proteins Orf6, Orf7a, and NSP6 interact with host cellular components to activatedeath receptor-mediated extrinsic apoptosis, involving TRAF2, TRADD, FADD, RIP, and cIAPs, which facilitate the activation ofcaspase-8. Caspase-8 further promotes apoptosis by cleaving downstream effector caspases, ultimately resulting in widespreadlung epithelial cell deathandpulmonary injury. This mechanistic insight underscores the pathological impact of SARS-CoV-2 on lung tissues and highlights potential therapeutic targets to mitigate severe COVID-19 outcomes.

Figure 3. The cGAS-STING signaling pathway in immune responses to SARS-CoV-2 and DNA.

SARS-CoV-2 or endosome-encapsulated DNA, activates cyclic GMP-AMP synthase (cGAS), leading to the production of cyclic GMP-AMP (cGAMP). cGAMP binds to the stimulator of interferon genes (STING), triggering a signaling cascade. STING activation recruits and stimulates transcription factors, including IRF3, NF-κB, and IRF7, resulting in the production of type I interferons (IFNs) and pro-inflammatory cytokines such as IL-6 and TNF. This pathway is essential in mounting an innate immune response to viral infections and cytosolic DNA. The figure illustrates STING agonists, including diABZI diacylbenzimidazole), diABZI-4, CF501, mucoadhesive nanoparticles, SIAPA (stimulator of interferon genes-activating polymeric agents), and Mn Jelly (manganese jelly), which enhance antiviral immunity by activating the cGAS-STING pathway.

Figure 4. Depiction of the innate immune signalling pathway, focusing on RIG-I/MDA-5/MAVS and their inhibition by SARS-CoV-2 proteins.

The pathway begins with the recognition of viral double-stranded RNA (dsRNA) by RIG-I-like receptors, including RIG-I and MDA-5, triggering a cascade of immune responses. Activation of MAVS (mitochondrial antiviral signalling protein) leads to downstream signalling involving MyD88, IRAK1/4, and NAP1, resulting in the activation of transcription factors such as IRF3, IRF7, IRF9, and NF-κB subunits (p50/65). This activation promotes the production of interferons (via IFNAR1 signalling) and interferon-stimulated genes (ISGs), critical for antiviral responses. The figure also highlights SARS-CoV-2 protein inhibitors, including non-structural proteins (NSPs) and open reading frames (ORFs), which interfere with various signalling components, such as MAVS and IRF pathways, to suppress immune activation. Additionally, key molecules like angiotensin-converting enzyme 2 (ACE2), neuropilin 1 (NRP1), and receptor-interacting serine/threonine kinase 1 (IkB) kinases (IKKα/β/γ/ɛ) are illustrated, emphasizing their roles in the pathway.